Sepsis Carcillo

Special Article

Clinical practice parameters for hemodynamic support of pediatricand neonatal patients in septic shock*

Joseph A. Carcillo, MD; Alan I. Fields, MD; Task Force Committee Members

Outcomes in neonatal and pe-diatric sepsis have improvedwith the advent of neonataland pediatric intensive care

(reduction in mortality from 97% to 9%)(1–3) and are markedly better than inadults (9% compared with 28% mortality)(3). The clinical practice parameters pre-sented in this document are an attempt toprovide a consensus statement on state-of-the-art hemodynamic support for neonates,infants, and children with septic shock.This document is designed to be an adden-dum to the previously published practice

parameters for hemodynamic support ofadult sepsis (4). The reader who is in searchof more detailed discussion of general prin-ciples in sepsis and cardiovascular support,or a more extensive reference list that con-centrates on adult animal and human lit-erature, is directed to this comprehensivedocument (4).

More than 30 clinical investigatorsand clinicians who were affiliated withthe Society of Critical Care Medicine andwho had special interest in hemodynamicsupport of pediatric patients with sepsis,were contacted and volunteered to be

members of the task force. Three inviteesdeclined to participate. Subcommitteeswere formed to review and grade the lit-erature by using the evidence-based scor-ing system of the American College ofCritical Care Medicine. The literature wasaccrued by using MEDLINE and indexingthe following age-limited keywords: sep-sis, septicemia, septic shock, endotox-emia, persistent pulmonary hyperten-sion, nitric oxide, and extracorporealmembrane oxygenation (ECMO). Theclinical parameters and guidelines weredrafted by using a modification of theDelphi method. Briefly, the initial stepincluded review of the literature andgrading of the evidence by topic-basedsubcommittees during a 1-yr period. Ofinterest, the committee found only fourrandomized controlled trials in childrenthat examined the effect of a hemody-namic support therapy on outcome fromseptic shock (5–8). Because of the pau-

*See also p. 1400.From the American College of Critical Care Medi-

cine.The American College of Critical Care Medicine,

which honors individuals for their achievements and con-tributions to multidisciplinary critical care medicine, is theconsultative body of the Society of Critical Care Medicinethat possesses recognized expertise in the practice ofcritical care. The College has developed administrative

guidelines and clinical practice parameters for the criticalcare practitioner. New guidelines and practice parame-ters are continually developed, and current ones aresystematically reviewed and revised.

Address requests for reprints to: Joseph A. Carcillo, MD,Children’s Hospital of Pittsburgh, Division of Critical CareMedicine, 3705 Fifth Avenue, Sixth Floor, Pittsburgh, PA15213. E-mail: [email protected]

Copyright © 2002 by Lippincott Williams & Wilkins

Background: The Institute of Medicine has called for the de-velopment of clinical guidelines and practice parameters to de-velop “best practice” and potentially improve patient outcome.

Objective: To provide American College of Critical Care Medi-cine clinical guidelines for hemodynamic support of neonates andchildren with septic shock.

Setting: Individual members of the Society of Critical CareMedicine with special interest in neonatal and pediatric septicshock were identified from literature review and general solici-tation at Society of Critical Care Medicine Educational and Sci-entific Symposia (1998–2001).

Methods: The MEDLINE literature database was searched withthe following age-specific keywords: sepsis, septicemia, septicshock, endotoxemia, persistent pulmonary hypertension, nitricoxide, and extracorporeal membrane oxygenation. More than 30experts graded literature and drafted specific recommendationsby using a modified Delphi method. More than 30 more expertsthen reviewed the compiled recommendations. The task-forcechairman modified the document until <10% of experts disagreedwith the recommendations.

Results: Only four randomized controlled trials in children withseptic shock could be identified. None of these randomized trialsled to a change in practice. Clinical practice has been based, for

the most part, on physiologic experiments, case series, andcohort studies. Despite relatively low American College of CriticalCare Medicine–graded evidence in the pediatric literature, out-comes in children have improved from 97% mortality in the 1960sto 60% in the 1980s and 9% mortality in 1999. U.S. hospitalsurvival was three-fold better in children compared with adults(9% vs. 27% mortality) in 1999. Shock pathophysiology and re-sponse to therapies is age specific. For example, cardiac failure isa predominant cause of death in neonates and children, butvascular failure is a predominant cause of death in adults. Ino-tropes, vasodilators (children), inhaled nitric oxide (neonates),and extracorporeal membrane oxygenation can be more impor-tant contributors to survival in the pediatric populations, whereasvasopressors can be more important contributors to adult sur-vival.

Conclusion: American College of Critical Care Medicine adult guide-lines for hemodynamic support of septic shock have little application tothe management of pediatric or neonatal septic shock. Studies arerequired to determine whether American College of Critical Care Medi-cine guidelines for hemodynamic support of pediatric and neonatalseptic shock will be implemented and associated with improved out-come. (Crit Care Med 2002; 30:1365–1378)

1365Crit Care Med 2002 Vol. 30, No. 6

city of outcome-directed, randomizedcontrolled trials, the recommendationsfor hemodynamic support of term new-borns and children in this document areprimarily expert opinion rather than ir-refutable evidence.

Subcommittees were formed to evaluateeach subtopic. The report from each sub-committee was compiled into a compre-hensive document by the task-force chair-person. All members commented on theunified draft, and modifications were madeuntil �10% of the task force disagreed withany specific or general recommendation.This process occurred during a 6-monthperiod. Reviewers from the American Col-lege of Critical Care Medicine then re-quested further modifications that wereperformed. The document was designed tomeet the maximum criteria possible as rec-ommended by the American Medical Asso-ciation. Grading of the literature and levelsof recommendations were based on pub-lished American College of Critical CareMedicine criteria (Table 1).

The task force did not follow the adultguideline format (4) because children haveage-specific considerations in hemody-namic support of septic shock. The taskforce drafted this document to providepractitioners with an expert opinion and anevidence-based, age-specific, stepwise ap-proach to hemodynamic support of septicshock in term neonates and children.

DEVELOPMENTALDIFFERENCES IN THEHEMODYNAMIC RESPONSE TOSEPSIS IN NEWBORNS,CHILDREN, AND ADULTS

The predominant cause of mortality inadult septic shock is vasomotor paralysis(9). Adults have myocardial dysfunctionmanifested as a decreased ejection frac-tion; however, cardiac output is usually

maintained or increased by two mecha-nisms, tachycardia and ventricular dila-tion. Adults who do not develop thisadaptive process to maintain cardiac out-put have a poor prognosis (10). Pediatricseptic shock is associated with severe hy-povolemia, and children frequently re-spond well to aggressive volume resusci-tation; however, the hemodynamicresponse of children who are fluid resus-citated seems diverse compared withadults. Contrary to the adult experience,low cardiac output, not low systemic vas-cular resistance, is associated with mor-tality in pediatric septic shock (11–20).Attainment of the therapeutic goal of acardiac index (CI) of 3.3–6.0 L/min/m2,may result in improved survival (20). Alsocontrary to adults, oxygen delivery, notoxygen extraction, is the major determi-nant of oxygen consumption in children(13). Attainment of the therapeutic oxy-gen consumption goal of >200 mL/min/m2 may also be associated with im-proved outcome (12).

It was not until 1998 that investiga-tors reported outcome when aggressivevolume resuscitation (60 mL/kg fluid inthe first hour) and goal-directed thera-pies (12) (CI goal of 3.3–6.0 L/min/m2

and normal pulmonary capillary occlu-sion pressure) were applied to childrenwith septic shock (20). Ceneviva et al.(20) described 50 children with fluid-refractory (�60 mL/kg in the first hour),dopamine-resistant shock. The majority(58%) showed a low cardiac output andhigh systemic vascular resistance state,and only 22% had low cardiac output andlow vascular resistance. Hemodynamicstates frequently progressed and changedduring the first 48 hrs. Persistent shockoccurred in 33% of the patients. Therewas a significant decrease in cardiac func-tion over time, requiring addition of ino-tropes and vasodilators. Although de-

creasing cardiac function accounted forthe majority of patients with persistentshock, some showed a complete changefrom a low output state to a high outputand low systemic vascular resistance state(21–24). Inotropes, vasopressors, and va-sodilators were directed to maintain nor-mal CI and systemic vascular resistancein the patients. Mortality from sepsis inthis study (18%) was markedly reducedcompared with mortality in the 1985study (58%) (12, 20), in which aggressivefluid resuscitation was not used.

Neonatal septic shock can be compli-cated by the physiologic transition fromfetal to neonatal circulation. In utero,85% of fetal circulation bypasses thelungs through the patent ductus arterio-sus and foramen ovale. This flow patternis maintained by suprasystemic pulmo-nary artery pressures prenatally. At birth,inhalation of oxygen triggers a cascade ofbiochemical events that ultimately resultin reduction in pulmonary artery pres-sure and transition from fetal to neonatalcirculation with blood flow now beingdirected through the pulmonary circula-tion. Closure of the patent ductus arteri-osus and foramen ovale complete thistransition. Pulmonary artery pressurescan remain elevated and the ductus arte-riosus can remain open for the first 6 wksof life, whereas the foramen ovale mayremain probe patent for years. Sepsis-induced acidosis and hypoxia can in-crease pulmonary artery pressure andmaintain patency of the ductus arterio-sus, resulting in persistent pulmonaryhypertension of the newborn (PPHN) andpersistent fetal circulation. Neonatal sep-tic shock with PPHN is associated withincreased right ventricle work. Despite inutero conditioning, the thickened rightventricle may fail in the presence of sys-temic pulmonary artery pressures. De-compensated right ventricular failure canbe clinically manifested by tricuspid re-gurgitation and hepatomegaly. Newbornanimal models of group B streptococcaland endotoxin shock have also docu-mented reduced cardiac output and in-creased pulmonary, mesenteric, and sys-temic vascular resistance (25–29).Therapies directed at reversal of rightventricle failure, through reduction ofpulmonary artery pressures, are com-monly needed in neonates with fluid re-fractory shock and PPHN.

The hemodynamic response in prema-ture, very low–birthweight infants withseptic shock (�32 wks gestation, �1000g) is least understood, in part, because

Table 1. American College of Critical Care Medicine guidelines for rating evidence-based medicine forstrength of recommendation and quality of evidence supporting the references

Rating system for referencesa: Randomized, prospective controlled trialsb: Nonrandomized, concurrent or historical cohort investigationsc: Peer-reviewed, state of the art articles, review articles, editorials, or substantial case seriesd: Non-peer reviewed published opinions, such as textbook statements or official organizational

publicationsRating system for recommendations

Level I: Convincingly justifiable on scientific evidence aloneLevel II: Reasonably justifiable by scientific evidence and strongly supported by expert critical

care opinionLevel III: Adequate scientific evidence is lacking but widely supported by available data and

expert opinion

1366 Crit Care Med 2002 Vol. 30, No. 6

pulmonary artery catheterization is notpossible in this population. Most infor-mation has been assessed from echocar-diographic evaluation alone. There is apaucity of studies devoted to septic shock.Literature is available, for the most part,on the hemodynamic response in prema-ture infants with respiratory distress syn-drome or shock of undescribed pathogen-esis. Echocardiographic analysis hasdocumented reduced right ventricularand left ventricular function in prema-ture newborns (30). This and other liter-ature indicates that premature infantswith shock can respond to volume andinotropic therapies with improvements instroke volume, contractility, and bloodpressure.

Several other developmental consider-ations influence therapies for shock. Rel-ative initial deficiencies in the thyroid,and parathyroid hormone axes have beenappreciated and can result in the need forthyroid hormone, calcium replacement,or both (31, 32). Hydrocortisone has beenexamined in this population as well (33).Immature mechanisms of thermogenesisrequire attention to external warming.Reduced glycogen stores and musclemass for gluconeogenesis require atten-tion to maintenance of serum glucose.Standard practices in resuscitation ofpremature infants in septic shock employa more graded approach compared withresuscitation of term neonates and chil-dren. This more cautious approach is aresponse to anecdotal reports that prema-ture infants at risk for intraventricularhemorrhage (�30 wks gestation) can de-velop hemorrhage after rapid shifts inblood pressure; however, some now ques-tion whether long-term neurologic out-comes are related to periventricular leu-komalacia (a result of prolongedunderperfusion) more than to intraven-tricular hemorrhage. Another complicat-ing factor in very low–birthweight in-fants is the persistence of the patentductus arteriosus. This can occur becauseimmature muscle is unable to constrict.The majority of infants with this condi-tion are treated medically with indometh-acin or surgically with ligation. Rapid ad-ministration of fluid may cause left-to-right shunting through the ductus, withensuing congestive heart failure inducedby ventricular overload. Studies of thera-pies specifically directed at prematurevery low–birthweight infants with septicshock are needed. One single-center, ran-domized controlled trial reported im-proved outcome with use of daily 6-hr

pentoxifylline infusions in very prema-ture infants with sepsis (5). This promis-ing therapy deserves evaluation in themulticentered trial setting (34).

WHAT CLINICAL SIGNS ANDHEMODYNAMIC VARIABLESCAN BE USED TO DIRECTTREATMENT OF NEWBORNAND PEDIATRIC SHOCK?

The University of Minnesota hospitalsreported a 97% mortality in children withGram-negative sepsis in 1963 (1). Withthe advent of modern pediatric intensivecare therapy, mortality has been reducedto 9% (3). The task-force consensus isthat early reversal of shock results inimproved outcome (35). In the absence ofsurvival-directed trials, the task forceagreed to evaluate the literature andmake recommendations on therapy byusing resolution of shock as the goldstandard outcome.

Shock can be defined by clinical vari-ables, hemodynamic variables, oxygenuse variables, or cellular variables. Afterreview of the literature, the committeechose to define septic shock by clinical,hemodynamic, and oxygen use variablesonly. Septic shock can be recognized, be-fore hypotension occurs, by a clinicaltriad that includes hypothermia or hyper-thermia, altered mental status, and pe-ripheral vasodilation (warm shock) orcool extremities (cold shock). Therapiesshould be directed to restoring normalmental status and peripheral perfusion.Restoration of urine output can also be areassuring measure of successful resusci-tation.

Shock should also be evaluated andresuscitated by using hemodynamic vari-ables. Flow (Q) varies directly with perfu-sion pressure (dP) and inversely with re-sistance (R). This is mathematicallyrepresented by Q � dP/R. For the wholebody, this is represented by cardiac out-put � mean arterial pressure (MAP) �central venous pressure (CVP)/systemicvascular resistance. This relationship isalso evident for organ perfusion. In thekidney, for example, renal blood flow �mean renal arterial pressure � mean re-nal venous pressure/renal vascular resis-tance. Some organs, including the kidneyand brain, have vasomotor autoregula-tion that maintains blood flow in lowblood pressure (MAP or renal arterialpressure) states. At some critical point,perfusion pressure is reduced below theability of the organ to maintain blood

flow. The purpose of treatment of shockis to maintain perfusion pressure abovethe critical point below which blood flowcannot be effectively maintained in indi-vidual organs. Because the kidney re-ceives the second highest blood flow ofany organ in the body, measurement ofurine output (with the exception of pa-tients with hyperosmolar states leadingto osmotic diuresis) and creatinine clear-ance can be used as an indicator of ade-quate perfusion pressure. In this regard,maintenance of MAP with norepineph-rine has been shown to improve urineoutput and creatinine clearance in hyper-dynamic sepsis (36). Maintenance of su-pranormal MAP above this point is likelynot of benefit (37)

Reduction in perfusion pressure belowthe critical point necessary for adequateorgan perfusion can also occur in diseasestates with increased intraabdominalpressure (IAP) such as bowel wall edema,ascites, or abdominal compartment syn-drome. Increased IAP is associated withincreased CVP. If this is not compensatedfor by an increase in MAP, then perfusionpressure is decreased. Therapeutic reduc-tion of IAP (measured by intrabladderpressure) results in restoration of perfu-sion pressure and has been shown to im-prove renal function in children withburn shock (38).

Shock can also be treated according tooxygen use measures. Measurement ofcardiac output and oxygen consumption(CI � [arterial oxygen content � mixedvenous oxygen]) has been proposed asbeing of benefit in patients with persis-tent shock because a CI between 3.3 and6.0 L/min/m2 and oxygen consumption�200 mL/min/m2 are associated with im-proved survival (12). Assuming a hemo-globin concentration of 10 g/dL and100% arterial oxygen saturation, then aCI of �3.3 L/min/m2 would correlate to amixed venous oxygen saturation of �70%in a patient with a normal oxygen con-sumption of 150 mL/min/m2 (oxygenconsumption � CI � arterial oxygencontent � oxygen extraction; therefore,150 mL/min/m2 � 3.3 L/min/m2 � [1.36� 10 g/dL � 100 � PaO2 � 0.003] �[100% � 70%]). Low cardiac output isassociated with mortality in pediatric sep-tic shock (11–20). In one study, childrenwith fluid-refractory dopamine-resistantshock were treated with goal-directedtherapy (CI, 3.3–6 L/min/m2) and foundto have predicted improved outcomescompared with historical reports (20).Low cardiac output is associated with in-


creased oxygen extraction (13). In anemergency room study in adults withseptic shock, maintenance of superiorvena cava oxygen saturation at �70% byuse of blood transfusion to a hemoglobinof 10 g/dL and inotropic support resultedin a 50% reduction in mortality com-pared with a group in which MAP-CVPwas maintained without attention to su-perior vena cava oxygen saturation (39).

DEVELOPMENTALCONSIDERATIONS INMONITORING AND TREATMENTOF SHOCK IN NEWBORNS ANDCHILDREN

Intravascular Access. Intravenous ac-cess for fluid resuscitation and inotrope-vasopressor infusion is more difficult toattain in newborns and children com-pared with adults. The American HeartAssociation and American Academy of Pe-diatrics have developed neonatal resusci-tation program and pediatric advancedlife support guidelines for emergency es-tablishment of intravascular support (40,41).

Fluid Therapy. Two clinical case serieshave evaluated fluid resuscitation in pe-diatric septic shock (19, 42). The larger ofthe two case series used a combination ofcrystalloid and colloid therapies (42).There is only one randomized controlledtrial comparing the use of colloid to crys-talloid resuscitation (dextran, gelatin,lactated Ringers, or saline) in childrenwith dengue shock (8). All these childrensurvived regardless of the fluid used, butthe longest time to recovery from shockoccurred in children who received Lac-tated Ringers. Among patients with thenarrowest pulse pressure, there was asuggestion that colloids were more effec-tive than crystalloids in restoring normalpulse pressure. On the basis of these andother studies, the committee agrees thatfluid resuscitation with crystalloids andcolloids is of fundamental importance tosurvival of septic shock (8, 19, 42–53).Debate on the efficacy of exclusive colloidresuscitation is ongoing. In a recent clin-ical practice position paper, a group cho-sen for outstanding results in resuscita-tion of meningococcal septic shock (5%mortality) reported that they use 5% al-bumin exclusively (20 mL/kg bolusesover 5–10 mins) and intubate all patientswho require �40 mL/kg (54). The Co-chrane Group meta-analysis that impliedharmful effects of colloid use in criticalillness evaluated no studies examining

fluid resuscitation in children or new-borns with septic shock. (55). Beneficialor harmful effects of colloids remain to bestudied in this population (56). The use ofblood as a fluid expander has been exam-ined in two small pediatric studies, butno recommendations were given by theinvestigators (57, 58). There are no pub-lished studies of or recommendations ontargeted hemoglobin concentration inchildren. The last National Institutes ofHealth consensus conference recom-mended a target hemoglobin concentra-tion of 10 g/dL in adults with cardiopul-monary compromise. An emergencyroom protocol directed to maintenance ofhemoglobin at 10 g/dL in adults with asuperior vena cava oxygen saturation of�70% was associated with improved out-comes (39).

Fluid infusion is best initiated withboluses of 20 mL/kg titrated to clinicalmonitors of cardiac output, includingheart rate, urine output, capillary refill,and level of consciousness. Large fluiddeficits typically exist, and initial volumeresuscitation usually requires 40 – 60mL/kg but can be as much as 200 mL/kg(19, 42–50). Patients who do not respondrapidly to initial fluid boluses, or thosewith insufficient physiologic reserve,should be considered for invasive hemo-dynamic monitoring. Filling pressuresshould be increased to optimize preloadto attain maximal cardiac output. In mostpatients, this will occur with a pulmonarycapillary occlusion pressure between 12and 15 mm Hg. Increases above thisrange usually do not significantly en-hance end-diastolic volume or stroke vol-ume and may be associated with de-creased survival. Large volumes of fluidfor acute stabilization in children havenot been shown to increase the rate of theacute respiratory distress syndrome (42,49) or cerebral edema (42, 50). Increasedfluid requirements may be evident forseveral days (19). Fluid choices includecrystalloids (normal saline) and colloids(dextran, gelatin, or 5% albumin) (8, 51–53, 55–58). Experience with the use ofstarch, hypertonic saline, or hyperoncoticalbumin was limited among members ofthe task force. Fresh-frozen plasma maybe infused to correct abnormal pro-thrombin time and partial thromboplas-tin time but should not be pushed be-cause it has hypotensive effects likelycaused by vasoactive kinins. In the ab-sence of data, it is reasonable to maintainhemoglobin concentration within thenormal range for age in children with

shock. Oxygen delivery depends signifi-cantly on hemoglobin concentration (ox-ygen delivery � CI � [1.36 � % hemo-globin � % oxygen saturation � PaO2 �0.003). Hemoglobin should be main-tained at a minimum of 10 g/dL (39).

Intravascular Catheters and Monitor-ing. Minimally invasive monitoring isnecessary in children with fluid-respon-sive shock; however, central vein accessand arterial pressure monitoring shouldbe considered and used in children withfluid-refractory shock. Maintenance ofperfusion pressure (MAP-CVP, or MAP-IAP if the abdomen is tense secondary tobowel edema or ascitic fluid) was consid-ered necessary for organ (particularly re-nal) perfusion (38). Echocardiographywas also considered an appropriate non-invasive tool to rule out the presence ofpericardial effusion. Superior vena cavaoxygen saturation of �70% is associatedwith improved outcome during the first 6hrs of presentation of septic shock(39).The decision to use pulmonary arterycatheter monitoring should be reservedfor those who remain in shock despitetherapies directed to clinical signs of per-fusion, MAP-CVP, and superior vena cavaoxygen saturation.

Consensus opinion on adult use of thepulmonary catheters has been summa-rized in the Society for Critical Care Med-icine Pulmonary Artery Catheter Con-sensus Conference document (59). Aclear reduction in mortality with pulmo-nary artery catheter use has not beendemonstrated in adults. We recommenduse of the pulmonary artery catheter inselected pediatric patients for the follow-ing reasons. Although the risk of pulmo-nary artery catheter–associated complica-tions exists, many published studiesevaluating use of hemodynamic supporttherapies in children have used the pul-monary catheter without reporting com-plications from its use (11–13, 15, 20, 42,57, 58, 60–64), supporting safety in thispopulation. A relatively large studyshowed that in children with fluid-refractory and dopamine-resistant shock,placement of the pulmonary artery cath-eter diagnosed improper cardiovascularsupport strategies that had been based onincorrect assessment of hemodynamicstate. This new information guided achange to appropriate therapies that re-versed shock (20), supporting potentialefficacy from pulmonary artery catheter–derived data in this population. An inde-pendent review of this topic interpretedthe results in this study to support the


use of the pulmonary artery catheter inthe select group of children with septicshock that has not been reversed by pe-ripheral arterial and CVP pressure andoxygen saturation– directed therapies(65). The committee concluded thatthere was not yet enough information orgeneral experience to recommend for oragainst the use of echocardiography, gas-tric tonometry, or femoral artery ther-modilution to direct therapy in childrenwith septic shock (60, 65–73).

Vasopressor Therapy. Dopamine re-mains the first-line vasopressor for highoutput, low vascular resistance shock inadults. Although the task force chose do-pamine as the first-line drug for fluid-refractory hypotensive shock in the set-ting of low systemic vascular resistance,it was also aware of the literature dem-onstrating an age-specific insensitivity todopamine (74–82). Dopamine causes va-soconstriction by releasing norepineph-rine from sympathetic vesicles. Imma-ture animals and young humans (�6months) may not have developed theirfull component of sympathetic vesicles.Dopamine-resistant shock commonly re-sponds to norepinephrine or high-doseepinephrine (20, 83, 84). Some in thecommittee promote use of low-dose nor-epinephrine as a first-line agent for warmhyperdynamic shock. Phenylephrine islimited to use as a pure vasopressor be-cause it has no ��adrenergic activity(85). Angiotensin or arginine vasopressincan be successful in patients who arerefractory to norepinephrine because itdoes not use the � receptor and its effi-cacy is therefore not affected by ongoing�-receptor down-regulation (86, 87). Useof vasopressors can be titrated to endpoints of perfusion pressure (MAP-CVP)or systemic vascular resistance that en-sure optimum urine output and creati-nine clearance (20, 36, 38, 83, 84). Nitricoxide inhibitors and methylene blue areconsidered investigational therapies (88–98).

Inotrope Therapy. As in adults, dobut-amine or mid-dosage dopamine can beused as the first line of inotropic support(20, 39, 99–110); however, children �12months can be less responsive (107). Do-butamine- or dopamine-refractory shockcan be reversed with epinephrine infu-sion (20, 110). Epinephrine is more com-monly used in children than in adults.Some members of the committee recom-mended use of low-dose epinephrine as afirst-line choice for cold hypodynamicshock. Recommendations in the adult lit-

erature have been driven by the observa-tion that epinephrine transiently reducesintramucosal pH in adults with hyperdy-namic sepsis (111), but there are no dataavailable to evaluate whether gut injurydoes or does not occur with epinephrineuse in children. Pediatric patients requir-ing inotropy are in a low cardiac output,not a high cardiac output, state.

When pediatric patients remain in anormotensive low cardiac output andhigh vascular resistance state, despiteepinephrine and nitrosovasodilator ther-apy, then the use of milrinone (if liverdysfunction is present) or amrinone (ifrenal dysfunction is present) should bestrongly considered (62– 64, 112–115).Amrinone and milrinone are rarely usedin adults because catecholamine refrac-tory low cardiac output and high vascularresistance is so uncommon; however, thishemodynamic state can represent a ma-jor proportion of children with fluid-refractory, dopamine-resistant shock(20). These type III phosphodiesterase in-hibitors prevent hydrolysis of cyclic aden-osine monophosphate and thereforepotentiate the effect of �-receptor stimu-lation in cardiac and vascular tissue.Down-regulation of the �1 and �2 recep-tor can be overcome by these drugs. Fluidboluses are likely to be required if amri-none or milrinone are administered withloading doses. Although recommended inthe literature (62, 63), many in the com-mittee choose not to use boluses of am-rinone or milrinone. This group admin-isters the drugs as a continuous infusiononly, recognizing that it will take morethan four half-lives to reach a steady-stateeffect. Because of the long half-life elim-ination, these drugs should be discontin-ued at the first sign of tachyarrhythmias,hypotension, or diminished systemic vas-cular resistance. Hypotension-relatedtoxicity with these drugs can be poten-tially overcome by stopping epinephrineand beginning norepinephrine (62, 63).Norepinephrine counteracts the effects ofincreased cyclic adenosine monophos-phate in vascular tissue by stimulatingthe � receptor. Norepinephrine accom-plishes this without further �2 stimula-tion.

Vasodilator Therapy. The use of vaso-dilators can reverse shock in pediatricpatients who remain hypodynamic with ahigh systemic vascular resistance state,despite fluid resuscitation and implemen-tation of inotropic support (20, 116–119).Most in the committee use nitrosovaso-dilators (nitroprusside or nitroglycerin

have a very short half-life elimination) asfirst-line therapy for children with epi-nephrine-resistant low cardiac outputand elevated systemic vascular-resistanceshock because hypotension-associatedtoxicity can be immediately reversed bystopping the infusion. Milrinone or am-rinone can be used for their vasodilatingproperties in patients with nitrosovasodi-lator-resistant, low-output syndrome ornitrosovasodilator-associated toxicity (cy-anide or isothiocyanate toxicity from ni-troprusside or methemoglobin toxicityfrom nitroglycerin) (20, 62, 63). Othervasodilators used and reported in neona-tal and pediatric septic shock includeprostacyclin, phentolamine, pentoxifyl-line, and dopexamine (120–123).

Glucose, Calcium, Thyroid, and Hy-drocortisone Replacement. It is impor-tant to maintain metabolic and hor-monal homeostasis in newborns andchildren. Hypoglycemia can cause neu-rologic devastation when missed. Hypo-glycemia must be rapidly diagnosed andpromptly treated. Hypocalcemia is afrequent, reversible contributor to car-diac dysfunction (32, 124, 125). Cal-cium replacement should be directed tonormalize ionized calcium levels. Thecommittee agreed that replacementwith thyroid or hydrocortisone could belifesaving in children with thyroid oradrenal insufficiency and catechol-amine-resistant shock (6, 7, 20, 31,124 –134). Infusion therapy with tri-iodothyronine has been shown to bebeneficial in postoperative patients withcongenital heart disease but has yet tobe studied in children with septic shock(135). Hypothyroidism can be com-monly found in children with trisomy21 and children with central nervoussystem disease (e.g., pituitary abnor-mality) (128).

The adult literature is examining theuse of hydrocortisone in patients withcatecholamine-dependent septic shockwithout adrenal insufficiency. The adultliterature is also exploring new defini-tions of relative hypoadrenal responses inseptic shock (129–141) (Table 2). Ourcommittee consensus was that until sim-ilar pediatric studies are performed, hy-drocortisone (not methylprednisolone)therapy should be reserved for use inchildren with catecholamine resistanceand suspected or proven adrenal insuffi-ciency. Adrenal insufficiency, and partic-ularly a low aldosterone state, may bemore common in children with septicshock than previously thought (127–129,


134, 135). Patients at risk include chil-dren with purpura fulminans and asso-ciated Waterhouse-Friedrichson syn-drome, children who have previouslyreceived steroid therapies for chronicillness, and children with pituitary oradrenal abnormalities (128). The com-mittee chose the most conservative di-agnostic approach and defines adrenalinsufficiency as a total cortisol level be-tween 0 and 18 mg/dL (138, 139). Re-view of the pediatric literature foundseveral case series and two randomizedtrials that used “shock dose” hydrocor-tisone in children (6, 7). The first ran-domized controlled trial showed im-proved outcome with hydrocortisonetherapy in children with dengue shock.The second study was underpoweredand showed no effect of hydrocortisonetherapy on outcome in children withdengue shock. The reported shock doseof hydrocortisone is 25 times higherthan the stress dose (6, 7, 133–141).

Therapy for PPHN. Although inhalednitric oxide therapy is the treatment ofchoice for uncomplicated PPHN (142, 143),the committee agreed that metabolic alka-linization remains an important initial re-suscitative strategy during shock (144).PPHN in the setting of septic shock canreverse when acidosis is corrected. For cen-ters with access to inhaled nitric oxide, thisis the only selective pulmonary vasodilatorreported to be effective in reversal of PPHN(142, 143, 145–150). ECMO remains thetherapy of choice for patients with refrac-tory PPHN and sepsis (151–154).

ECMO Therapy. ECMO is not routinelyused in adults (with the notable exceptionof the University of Michigan) (151). How-ever, ECMO is a viable therapy for refrac-tory shock in neonates (151–154). The Ex-tracorporeal Life Support Organizationregistry suggests that neonates have a sim-ilar outcome (survival rate of approxi-mately 80%) whether the indication forECMO is refractory respiratory failure orrefractory shock. Although the outcome issimilar, neonates with septic shock havemore complications (e.g., bleeding and in-fection) associated with therapy. The Extra-corporeal Life Support Organization regis-try and other reports in the literaturesuggest outcome is less successful whenECMO is used for refractory pediatric septicshock (37% to 50% survival) (155–157).Therefore, the committee agreed thatits use in pediatric septic shock is lesssuccessful, yet it seems to be reasonableaccording to clinical judgment. Of in-terest, ECMO is effective for pediatric

cardiogenic shock (158). It is also effec-tive in adult victims of hantavirus withlow cardiac output and high systemicvascular resistance shock (159 –160).The committee speculates that ECMOtherapy is likely most successful in pa-tients with refractory low cardiac out-put septic shock.

RECOMMENDATIONS FORPEDIATRIC SEPTIC SHOCK

Diagnosis

The inflammatory triad of fever, tachy-cardia, and vasodilation is common in

children with benign infections. Septicshock is suspected when children withthis triad have a change in mental statusmanifested as inconsolable irritability,lack of interaction with parents, or inabil-ity to be aroused (Fig. 1). The clinicaldiagnosis of septic shock is made in chil-dren who have a suspected infectionmanifested by hypothermia or hyperther-mia and have clinical signs of decreasedperfusion, including decreased mentalstatus, prolonged capillary refill of �2secs (cold shock) or flash capillary refill(warm shock), diminished (cold shock) orbounding (warm shock) peripheral

Figure 1. Recommendations for stepwise management of hemodynamic support in infants andchildren with goals of normal perfusion and perfusion pressure (mean arterial pressure � centralvenous pressure [MAP � CVP]). Proceed to next step if shock persists. PALS, pediatric advanced lifesupport; PICU, pediatric intensive care unit; SVC O2, superior vena cava oxygen; PDE, phosphodies-terase; CI, cardiac index; ECMO, extracorporeal membrane oxygenation.

Table 2. Definitions of shock

Cold or warm shock: Decreased perfusion including decreased mental status, capillary refill �2secs (cold shock) or flash capillary refill (warm shock), diminished (cold shock) or bounding(warm shock) peripheral pulses, mottled cool extremities (cold shock), or decreased urine output�1 mL/kg/hr

Fluid-refractory/dopamine-resistant shock: Shock persists despite �60 mL/kg fluid resuscitation infirst hour and dopamine infusion to 10 g/kg/min

Catecholamine resistant shock: Shock persists despite use of catecholamines epinephrine ornorepinephrine

Refractory shock: Shock persists despite goal-directed use of inotropic agents, vasopressors,vasodilators, and maintenance of metabolic (glucose and calcium) and hormonal (thyroid andhydrocortisone) homeostasis


pulses, mottled cool extremities (coldshock), or decreased urine output of �1mL/kg/hr. Hypotension is not necessaryfor the clinical diagnosis of septic shock;however, its presence in a child with clin-ical suspicion of infection is confirma-tory.

ABCs: First Hour ofResuscitation

Goals (Level III).

Maintain airway, oxygenation, and ven-tilation

Maintain circulation (defined as nor-mal perfusion and blood pressure)

Maintain threshold heart rates (Table3)

Therapeutic End Points (Level III).Therapeutic end points include capillaryrefill of �2 secs, normal pulses with nodifferential between peripheral and cen-tral pulses, warm extremities, urine out-put �1 mL/kg/hr, normal mental status,and normal blood pressure for age.

Monitoring (Level III).

Pulse oximeter

Continuous electrocardiography

Blood pressure

Temperature

Urine output

Glucose and ionized calcium

Airway and Breathing (Level III). Air-way and breathing should be rigorouslymonitored and maintained. Lung compli-ance and work of breathing may changeprecipitously. Patients typically manifesthypoxemia and metabolic acidosis andare at high risk to develop respiratoryacidosis. The decision to intubate andventilate is made on clinical diagnosis ofincreased work of breathing, hypoventi-lation, impaired mental status, or pres-ence of a moribund state. Waiting for

confirmatory laboratory tests is discour-aged. Volume loading may be requiredduring intubation because of relative orabsolute hypovolemia. Induction agentsthat maintain cardiovascular integrityshould be used.

Circulation (Level II). Vascular accessshould be rapidly attained. Establish in-traosseous access if reliable venous accesscannot be rapidly attained. Placement ofcentral catheter access will usually be re-quired for vasoactive infusions.

Fluid Resuscitation (Level II). Rapidfluid boluses of 20 mL/kg (isotonic salineor colloid) should be administered bypush while observing for the develop-ment of rales, gallop rhythm, hepatomeg-aly, and increased work of breathing. Inthe absence of these clinical findings,fluid can be administered to as much as200 mL/kg in the first hour. The averagerequirement is 40–60 mL/kg in the firsthour. Fluid should be pushed with thegoal of attaining normal perfusion andblood pressure.

Hemodynamic Support (Level II). Pa-tients with severe shock uniformly re-quire vasoactive support during fluid re-suscitation. Vasoactive agents should beadministered when a second catheter,preferably a central catheter, has beenestablished. Dopamine can be used as thefirst-line agent; however, dopamine-resistant shock should be quickly recog-nized and epinephrine used for coldshock or norepinephrine used for warmshock to restore normal perfusion andblood pressure.

Hydrocortisone Therapy (Level III).Adrenal insufficiency should be suspectedin catecholamine-resistant hypotensiveshock in children with a history of CNSabnormality or chronic steroid use orwith purpura fulminans. Use of hydrocor-tisone in this situation may be lifesaving.Dose recommendations vary from a bolusof 1–2 mg/kg for stress coverage to 50

mg/kg for shock, followed by the samedose as a 24-hr infusion.

Stabilization: Beyond the FirstHour

Goals (Level III).

Normal perfusion

Perfusion pressure (MAP-CVP or MAP-IAP) appropriate for age

Superior vena cava or mixed venousoxygen saturation of �70%

CI of �3.3 L/min/m2 and �6.0L/min/m2

Therapeutic End Points (Level III).Therapeutic end points are capillary refillof �2 secs, normal pulses with no differ-ential between peripheral and centralpulses, warm extremities, urine output�1 mL/kg/hr, normal mental status, CI�3.3 and �6.0 with normal perfusionpressure (MAP-CVP or MAP-IAP) for age,and superior vena cava or mixed venousoxygen saturation �70%. Maximize pre-load to maximize CI.


Pulse oximetry


Continuous intraarterial blood pres-sure

Temperature

Urine output

Central venous pressure and oxygensaturation

Pulmonary artery pressure and oxygensaturation

Cardiac output

Glucose and calcium

Fluid Resuscitation (Level II). Fluidlosses and persistent hypovolemia sec-ondary to diffuse capillary leak can con-tinue for days. Ongoing fluid replacementshould be directed at clinical end points,including perfusion, pulmonary capillaryocclusion pressure, and cardiac output.Crystalloid is the fluid of choice in pa-tients with hemoglobin �10 g/dL. Packedred blood cell transfusion can be given tochildren with hemoglobin �10 g/dL.

Hemodynamic Support (Level II). He-modynamic support can be required fordays in children with fluid-refractoryshock. Children can present with low car-diac output and high systemic vascularresistance, high cardiac output and lowsystemic vascular resistance, or low car-diac output and low systemic vascular

Table 3. Threshold heart rates and perfusion pressure (MAP-CVP or MAP-IAP) for agea

Term Newborn (yrs) Heart Rate (beats/min) MAP-CVP (cm H2O)

120–180 55�1 120–180 60�2 120–160 65�7 100–140 65�15 90–140 65

MAP-CVP, mean arterial pressure–central venous pressure.aAdapted with permission from Johnson KB: The Harriet Lane Handbook. 13th Edition. St. Louis,

Mosby Year-Book, 1993; and Report of the Second Task Force on Blood Pressure Control in Children–1987 (161, 162).


resistance shock. Although children withpersistent shock frequently have worsen-ing cardiac failure, hemodynamic statesmay completely change over time. A pul-monary artery catheter should be placedwhen poor perfusion, including reducedurine output, acidosis, or hypotension,persists despite use of hemodynamictherapies guided by clinical examination,blood pressure analysis, echocardio-graphic analysis, and arterial and supe-rior vena cava oxygen saturation analysis.Children can respond to a change in he-modynamic therapeutic regimen withresolution of shock. Therapies should beadjusted to maintain mixed venous oxy-gen saturation �70%, CI of �3.3 L/min/m2, and a normal perfusion pressure forage (MAP-CVP), with the ultimate goal ofrestoration of normal perfusion. There isno benefit to increasing oxygen deliverybeyond the point of oxygen consumptionplateau (critical point of oxygen delivery).

Shock with Low CI (Level II). Epi-nephrine is usually the first-line drug fordopamine-resistant shock. If hemody-namics are dependent on epinephrineand the cortisol level is �18 mg/dL, hy-drocortisone at stress or shock doses maybegin. If T4 or T3 level is low and sickeuthyroid syndrome has been excluded,oral levothyroxine or, if necessary, intra-venous liothyronine can be used to re-store normal values for age.

Shock with Low CI, Normal BloodPressure, and High Systemic VascularResistance (Level II). Nitroprusside or ni-troglycerin are first-line vasodilators inpatients with epinephrine-resistant shockand normal blood pressure. If cyanide orisothiocyanate toxicity develops from ni-troprusside, or methemoglobin toxicitydevelops from nitroglycerin, or there is acontinued low cardiac output state, thenthe clinician should substitute milrinoneor amrinone. As noted above, the longhalf-life elimination of these drugs canlead to slowly reversible toxicities (hypo-tension or tachyarrhythmias), particu-larly if abnormal renal or liver functionexists. Such toxicities can be reversed inpart with norepinephrine infusion. Addi-tional volume loading is necessary to pre-vent hypotension when loading doses areused.

Shock with High CI and Low SystemicVascular Resistance (Level II). Norepi-nephrine is the drug of choice forage-dependent dopamine resistance. Ifhemodynamics are dependent on norepi-nephrine and the cortisol levels are �18mg/dL, then hydrocortisone at stress or

shock doses may be initiated. If the T4 orT3 level is low and sick euthyroid syn-drome is excluded, then oral thyroxineor, if necessary, intravenous liothyroninecan be given.

Refractory Shock (Level II). Childrenwith catecholamine-refractory shockmust be suspected to have unrecog-nized morbidities, including pericardialeffusion, pneumothorax, hypoadrenal-ism, hypothyroidism, ongoing bloodloss, intraabdominal catastrophe, ne-crotic tissue, and others. When thesemorbidities have been excluded, ECMObecomes an important alternative toconsider. Currently, however, the ex-pected survival is no greater than 50%.If the clinician suspects that outcomewill be better with ECMO, flows �110mL/kg may be required if vasodilationexists. Calcium concentration shouldbe normalized in the red blood cellpump prime (usually requires 300 mgof CaCl2 per unit of packed red bloodcells).

RECOMMENDATIONS FORNEWBORN SEPTIC SHOCK

Diagnosis

Septic shock should be suspected inany newborn with respiratory distressand reduced perfusion, particularly in thepresence of a maternal history of chorio-amnionitis or prolonged rupture of mem-branes. It is important to distinguishnewborn septic shock from cardiogenicshock caused by closure of the patentductus arteriosus in newborns with duc-tal dependent complex congenital heartdisease. Any newborn with shock andhepatomegaly, cyanosis (a cardiac mur-mur), or differential upper and lower ex-tremity blood pressures or pulses shouldbe started on prostaglandin E1 until com-plex congenital heart disease is ruled outby echocardiographic analyses. Newbornseptic shock is typically accompanied byincreased pulmonary artery pressures.Persistent pulmonary hypertension cancause right ventricle failure (Fig. 2).

Figure 2. Recommendations for stepwise management of hemodynamic support in term newbornswith goals of normal perfusion and perfusion pressure (mean arterial pressure � central venouspressure) and preductal and postductal oxygen saturation difference of �5%. Proceed to next step ifshock persists. RDS, respiratory distress syndrome; NRP, neonatal resuscitation program; NICU,neonatal intensive care unit; PPHN, pulmonary hypertension of the newborn; CVP, central venouspressure; LV, left ventricular; RV, right ventricular; PDE, phosphodiesterase; ECMO, extracorporealmembrane oxygenation.


ABCs: First Hour ofResuscitation

Goals (Level III).

Maintain airway, oxygenation, and ven-tilation

Maintain circulation (defined as nor-mal perfusion and blood pressure)

Maintain neonatal circulation

Maintain threshold heart rates

Therapeutic End Points (Level III).Therapeutic end points include capillaryrefill of �2 secs, normal pulses with nodifferential between peripheral and cen-tral pulses, warm extremities, urine out-put of �1 mL/kg/hr, normal mental sta-tus, normal blood pressure for age,difference in preductal and postductal ox-ygen saturation of �5%, and oxygen sat-uration of �95%.


Temperature

Preductal and postductal pulse oxime-try

Intra-arterial (umbilical or peripheral)blood pressure


Blood pressure

Arterial pH

Urine output

Glucose and calcium

Airway and Breathing (Level III). Air-way and breathing should be rigorouslymonitored and maintained. The decisionto intubate and ventilate is made on clin-ical diagnosis of increased work ofbreathing or the moribund state. Volumeloading is necessary during intubationand ventilation because of hypovolemia.

Circulation (Level III). Vascular accessshould be rapidly attained according toNRP. Placement of an umbilical arterialand venous catheter is preferred. If thesecatheters cannot be placed, a peripheralarterial and peripherally positioned cen-tral catheter can be placed.

Fluid Resuscitation (Level II). Rapidfluid boluses of 10 mL/kg should be ad-ministered, observing for the develop-ment of rales, hepatomegaly, and in-creased work of breathing. Up to 60mL/kg may be required in the first hour.Fluid should be pushed, with a goal ofattaining normal perfusion and bloodpressure.

Hemodynamic Support (Level II). Pa-tients with severe shock uniformly re-

quire vasoactive support during fluid re-suscitation. Although dopamine can beused as the first-line agent, its effect onpulmonary vascular resistance should betaken into account. Usually, a combina-tion of dopamine at low dosage (�8 mg/kg/min) and dobutamine (up to 30 g/kg/min) is used; if the patient is notresponsive to therapy, then epinephrineshould be infused to restore normal bloodpressure and perfusion.

PPHN Therapy (Level II). Hyperoxy-genate initially with 100% oxygen, andinstitute metabolic alkalinization (up topH 7.50) with NaHCO3 or tromethamine.Mild hyperventilation can also be insti-tuted until 100% oxygen saturation and�5% difference in preductal and post-ductal saturations are obtained. Thera-peutic narcosis with fentanyl and paraly-sis with neuromuscular blockers shouldbe considered to reduce pulmonary bloodpressures in ventilated patients withoutresponse to the PPHN therapy outlinedabove. Inhaled nitric oxide should be ad-ministered when available.

Stabilization: Beyond the FirstHour

Goals (Level III).

Maintain threshold heart rate

Maintain normal perfusion and bloodpressure

Maintain neonatal circulation

Central venous oxygen saturation�70%

Therapeutic End Points (Level III).

Capillary refill �2 secs, normal pulseswith no differential between peripheraland central pulses, warm extremities,urine output �1 mL/kg/hr, normalmental status, normal blood pressurefor age

�95% peripheral oxygen saturation

�5% difference in preductal and post-ductal saturation

Central venous oxygen saturation�70%

Absence of right-to-left shunting, tri-cuspid regurgitation, or right ventric-ular failure on echocardiographic anal-ysis


Pulse oximetry

Arterial pH


Continuous intra-arterial blood pres-sure

Temperature

Glucose and calcium

Urine output

Central venous pressure and oxygensaturation

Fluid Resuscitation (Level II). Fluidlosses and persistent hypovolemia sec-ondary to diffuse capillary leak can con-tinue for days. Ongoing fluid replacementshould be directed at clinical end points,including perfusion and CVC. Crystalloidis the fluid of choice in patients withhemoglobin �12 g/dL. Packed red bloodcell transfusion can be added in newbornswith hemoglobin �12 g/dL.

Hemodynamic Support (Level II). Thepulmonary vascular reactivity will tend todecrease after 5 days of life, although thisshould be evaluated carefully before stop-ping therapies directed at PPHN. In thepatient with suprasystemic pulmonaryhypertension, right ventricle failure mayaccompany shock. This can make ino-trope and vasopressor therapies less effec-tive at supporting cardiac output. Thera-pies directed at reducing pulmonaryartery pressure are paramount. Inhalednitric oxide can be given with greatesteffects usually found at 20 ppm. In new-borns with poor left ventricle functionand normal blood pressure, the additionof nitrosovasodilators or type III phos-phodiesterase inhibitors can be effectivebut must be monitored for toxicities. It isimportant to volume load when usingthese systemic vasodilators.

ECMO Therapy for Refractory Shock(Level II). Newborns with refractoryshock must be suspected to have unrec-

T he task force

drafted this docu-

ment to provide

practitioners with an expert

opinion and an evidence-

based, age-specific, stepwise

approach to hemodynamic

support of septic shock in

term neonates and children.


ognized morbidities, including pericar-dial effusion, pneumothorax, ongoingblood loss, hypoadrenalism, hypothyroid-ism, inborn errors of metabolism, or cy-anotic or obstructive heart disease. Whenthese causes have been excluded, ECMObecomes an important therapy to con-sider. The expected ECMO survival ratefor newborn septic shock is currently80%. Most centers accept refractoryshock or a PaO2 �40 mm Hg after max-imal therapy to be sufficient indicationfor ECMO support. ECMO flows of �110mL/kg may be required when vasodila-tion exists. When administering venoar-terial ECMO, persistent hypotension orshock should be treated with dopamineor epinephrine because vasodilation isthe likely cause. The venoarterial systemprovides inotropic support. Inotrope re-quirements frequently lessen when veno-arterial ECMO is used. Calcium concen-tration should be normalized in the redblood cell pump prime (usually requires300 mg of CaCl2 per unit of packed redblood cells).

ACKNOWLEDGMENT

We thank Charm Kohlenberger for as-sistance.

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APPENDIX

This article was prepared by the follow-ing authors: American College of CriticalCare Medicine Task Force Chairperson,Joseph A. Carcillo, MD (Pittsburgh, PA);American College of Critical Care MedicineTask Force Committee Members, DebbieBills, RN (Pittsburgh, PA), Desmond J.Bohn, MB, BS (Toronto, Canada), RobertBoxer, MD (Roslyn, NY), Richard Brilli, MD(Cincinnati, OH), Cynthia W. Broner, MD,(Columbus, OH), Juan Casado-Flores, MD(Madrid, Spain), Leticia Castillo, MD (Bos-ton, MA), Gary D. Ceneviva, MD (Hershey,PA), Reuben Cohen, MD, Andrew T.Costarino, MD (Wilmington, DE), Heidi J.Dalton, MD (Washington, DC), Alan L.Davis, MD (Summit, NJ), Lesley A.Doughty, MD (Providence, RI), MichelleDragotta, RN (Pittsburgh, PA), Alan W.Duncan (Perth, Australia), Elizabeth A.Farrington, PharmD (Durham, NC),Timothy F. Feltes, MD (Columbus, OH),Brett P. Giroir, MD (Dallas, TX), BrahmGoldstein, MD (Portland, OR), BruceGreenwald, MD (New York, NY), Mark Hall,MD (Columbus, OH), Yong Y. Han (Pitts-burgh, PA), Steven E. Haun, MD (SiouxCity, SD), Gabriel J. Hauser, MD (Washing-ton, DC), Jan Hazelzet, MD (Rotterdam,The Netherlands), Sabrina Heidemann, MD(Detroit, MI), Lyn Hernan, MD (Buffalo,NY), Ronald B. Hirschl, MD (Ann Arbor,MI), Steven A. Hollenberg, MD (Chicago,IL), Jorge Irazusta, MD (Boston, MA), BrianJacobs, MD (Cincinnati, OH), Stephen R.Johnson, MD, (Los Angeles, CA), RobertKanter, MD (Syracuse, NY), Carol King,MD (Buffalo, NY), Erica Kirsch, MD (Dallas,TX), Jacques LaCroix, MD (Montreal, Can-ada), Stephen A. Lawless, MD (Wilmington,DE), Francis LeClerc, MD (Lille, France),Steven E. Lucking, MD (Hershey, PA), LucyLum, MD (Kuala Lumpur, Malaysia), M.Michele Mariscalco, MD (Houston, TX),Professor Jean-Christophe Mercier (Paris,France), Richard B. Mink, MD (Los Angeles,CA), M. Michelle Moss, MD (Little Rock,AR), Daniel A. Notterman, MD (Newark,NJ), William Novotny, MD (Greenville, NC),Kristan M. Outwater, MD (Saginaw, MI),Hector S. Pabon, MD (Brandon, FL),Margaret M. Parker, MD (Stonybrook, NY),J. Alan Paschall, MD (Takoma, WA),Jefferson P. Piva, MD (Porto Alegre, Brazil),Ronald M. Perkin, MD (Greenville, NC),


Francois Proulx, MD (Montreal, Canada),Gerardo Reyes, MD (Oak Lawn, IL),Gustavo Rios, MD (Vina del Mar, Chile),Ricardo Ronco, MD (Santiago, Chile),Cathy H. Rosenthal-Dichter, MN, CCRN(Yorktown, IN), James Royall, MD (Oklaho-ma City, OK), Billie L. Short, MD (Wash-ington, DC), Rana Rozenfeld, MD (Chicago,

IL), Brian Rudinsky, MD (Chicago, IL),Ashok P. Sarnaik, MD (Detroit, MI), JorgeSasbon, MD (Buenos Aires, Argentina),Thomas Shanley, MD (Cincinnati, OH),Neil J. Thomas, MD (Hershey, PA), EduardoJuan Troster, MD (Sao Paolo, Brazil),Shekhar T. Venkataraman, MB, BS(Pittsburgh, PA), R. Scott Watkins, MD

(Pittsburgh, PA), Richard A. Orr, MD (Pitts-burgh, PA), Thomas M. Williams, MD (In-dianapolis, IN), Hector R. Wong, MD (Cin-cinnati, OH), Arno Zaritsky, MD(Gainesville, FL), and Jerry J. ZimmermanPhD, MD (Seattle, WA), and American Col-lege of Critical Care Medicine Liaison, AlanI. Fields, MD (Houston, TX).


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